Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol

Sonia M S Espirito Santo, Nuno M M Pires, Lianne S M Boesten, Gery Gerritsen, Niels Bovenschen, Ko Willems Van Dijk, J. Wouter Jukema, Hans M G Princen, André Bensadoun, Wei Ping Li, Joachim Herz, Louis M. Havekes, Bart J M Van Vlijmen

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

The low-density lipoprotein (LDL) receptor-related protein (LRP) has a well-established role in the hepatic removal of atherogenic apolipoprotein E (APOE)-rich remnant lipoproteins from plasma. In addition, LRP recognizes multiple distinct pro- and antiatherogenic ligands in vitro. Here, we investigated the role of hepatic LRP in atherogenesis independent of its role in removal of APOE-rich remnant lipoproteins. Mice that allow inducible inactivation of hepatic LRP were combined with LDL receptor and APOE double-deficient mice (MX1Cre+LRPflox/floxLDLR -/-APOE-/- On an LDLR-/-APOE-/- background, hepatic LRP deficiency resulted in decreased plasma cholesterol and triglycerides (cholesterol: 17.1 ± 5.2 vs 23.4 ± 6.3 mM, P = . 025; triglycerides: 1.1 ± 0.5 vs 2.2 ± 0.8 mM, P = .002, for MX1Cre+LRPflox/flox-LDLR-/-APOE-/- and control LRPflox/flox-LDLR-/-APOE-/- mice, respectively). Lower plasma cholesterol in MX1Cre+LRP flox/flox-LDLR-/-APOE-/- mice coincided with increased plasma lipoprotein lipase (71.2 ± 7.5 vs 19.1 ± 2.4 ng/ml, P = .002), coagulation factor VIII (4.4 ± 1.1 vs 1.9 ± 0.5 U/mL, P = .001), von Willebrand factor (2.8 ± 0.6 vs 1.4 ± 0.3 U/mL, P = .001), and tissue-type plasminogen activator (1.7 ± 0.7 vs 0.9 ± 0.5 ng/ml, P = .008) compared with controls. Strikingly, MX1Cre +-LRPflox/floxLDLR-/-APOE-/- mice showed a 2-fold higher atherosclerotic lesion area compared with controls (408. 5 ± 115.1 vs 219.1 ± 86.0 103μm2, P = .003). Our data indicate that hepatic LRP plays a clear protective role in atherogenesis independent of plasma cholesterol, possibly due to maintaining low levels of its proatherogenic ligands.

Original languageEnglish (US)
Pages (from-to)3777-3782
Number of pages6
JournalBlood
Volume103
Issue number10
DOIs
StatePublished - May 15 2004

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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